Long-term Safety and Efficacy of the Anti-MAdCAM-1 Monoclonal Antibody Ontamalimab [SHP647] for the Treatment of Ulcerative Colitis: The Open-label Study TURANDOT II.

BACKGROUND AND AIMS: Ontamalimab, a fully-human monoclonal antibody targeting MAdCAM-1, induced remission in patients with moderate-to-severe ulcerative colitis [UC] in the TURANDOT study. We aimed to assess long-term safety, tolerability, and efficacy of ontamalimab in TURANDOT II. METHODS: TURANDOT II was a phase 2, multicentre, open-label [OL] study in patients with moderate-to-severe UC who completed TURANDOT on placebo or ontamalimab (NCT01771809). Patients were randomised to 75 mg or 225 mg ontamalimab every 4 weeks for 72 weeks [OL1]. The dosage could be increased to 225 mg from Week 8 at the investigator's discretion. All patients then received 75 mg every 4 weeks for 72 weeks [OL2], followed by 6-month safety follow-up. The primary objective was safety, measured by adverse events [AEs], serious AEs [SAEs], and AEs leading to withdrawal. Mucosal healing [MH; centrally read endoscopy] was assessed. RESULTS: Of 330 patients, 180 completed OL1; 94 escalated to 225 mg; 127 completed OL2. Overall, 36.1% experienced drug-related AEs. The most common SAE [10.0%] was worsening/ongoing UC; 5.5% of patients had serious infections, the most common being gastroenteritis [0.9%]. One death and four cancers [all unrelated to ontamalimab] occurred. No PML [progressive multifocal leukoencephalopathy]/lymphoproliferative disorders occurred. Geometric mean high-sensitivity C-reactive protein [hsCRP] and faecal calprotectin decreased across OL1 in both dose groups. The proportion of patients assigned to placebo in TURANDOT achieving MH increased from 8.8% [6/68] at baseline to 35.3% at Week 16 [24/68; non-responder imputation]. The corresponding increase in the ontamalimab group was from 23.3% [61/262] to 26.7% [70/262]. CONCLUSIONS: Ontamalimab was well tolerated up to 144 weeks in patients with moderate-to-severe UC, with good safety and efficacy.

Phase 2: a dose-escalation study of OncoGel (ReGel/paclitaxel), a controlled-release formulation of paclitaxel, as adjunctive local therapy to external-beam radiation in patients with inoperable esophageal cancer.

OncoGel, a novel injectable formulation of paclitaxel in a biocompatible biodegradable gel (ReGel), provides controlled release of paclitaxel at the injection site, resulting in high intralesional paclitaxel concentrations and continuous radiosensitization without attendant systemic toxicities. This dose-escalation study evaluated the toxicity, pharmacokinetics, and preliminary antitumor activity of OncoGel injected intralesionally in patients with inoperable esophageal cancer who were candidates for palliative external-beam radiotherapy (RT). Eleven patients with inoperable advanced esophageal cancer received a single administration of OncoGel into the primary tumor using conventional endoscopic techniques. Three cohorts received approximately one-third of the tumor volume with increasing paclitaxel concentrations to achieve 0.48, 1.0, and 2.0 mg paclitaxel/cm tumor volume. Subsequent to injection, RT was initiated (50.4 Gy in 1.8 Gy fractions). Pharmacokinetic sampling was performed. All patients completed the study. No dose-limiting toxicities were reported. Dysphagia improved and tumor size decreased in most patients. Biopsies were negative for carcinoma in 4 of 11 patients. Peak paclitaxel plasma concentrations were low (0.53-2.73 ng/ml) and directly related to the absolute amount of paclitaxel administered. Paclitaxel was detectable in plasma for 24 h in all patients and for 3 weeks in six patients. OncoGel given as an adjunct to RT was well tolerated in patients with inoperable esophageal cancer and provided prolonged paclitaxel release with minimal systemic exposure. OncoGel plus RT seemed to reduce tumor burden as evidenced by dysphagia improvement, tumor size reduction, and negative esophageal biopsies. The addition of OncoGel to combined modality therapy merits continued clinical development.

Vedolizumab in the treatment of Crohn's disease.

Vedolizumab, a recent addition to the therapeutic armamentarium in Crohn's disease, is promising in efficacy, durability of remission and safety. It is the first gut selective biologic treatment, acting by targeting α4ß7-integrin, a receptor expressed on activated lymphocytes and binding to MAdCAM1, a cell adhesion molecule selectively expressed in the circulatory system of the digestive tract, preventing trafficking of lymphocytes to the gut. The pivotal GEMINI studies have demonstrated the efficacy and safety of vedolizumab in achieving clinical response and clinical remission in patients with moderately to severely active CD who are naïve or have previously failed therapy with TNF-antagonists, immunomodulators or dependent on steroids. Vedolizumab had a favorable safety profile and specifically showed no evidence of PML, reactivation of latent TB or hepatitis B. Overall, the number of malignancies in the clinical trials was small; however, long-term exposure was limited. Vedolizumab can be given as a first-line therapy or following treatment failure, and was tolerated as part of combination therapy. More medications with similar and novel therapeutic mechanisms are anticipated in the coming years.

Biochemical liver function test parameter levels in relation to treatment response in liver metastatic colorectal patients treated with FOLFOX4 with or without bevacizumab.

Introduction: Combined use of bevacizumab and conventional anticancer drugs leads to a significant improvement of treatment response in patients with metastatic colorectal carcinoma (CRC). Conventional treatment protocols exert undesired effects on the liver tissue. Hepatotoxic effects are manifested as a disturbance of liver function test parameters. The relation between clinical outcome and disorder of biochemical parameters has not been completely evaluated. Objective: The objective of our study was to examine whether clinical outcome in patients with liver metastatic CRC correlates with the level of liver function test parameters. Methods: The study included 96 patients with untreated liver metastatic CRC who received FOLFOX4 protocol with or without bevacizumab. Biochemical liver parameters were performed before and after the treatment completion. Treatment response was evaluated as disease regression, stable disease, and disease progression. The patients were divided into three groups according to the accomplished treatment response. Results: In the group of patients with disease regression the post-treatment levels of aspartate aminotransferase, alanine aminotransferase, and bilirubin were statistically significantly increased. In contrast to this, gamma-glutamyltransferase and protein post-treatment values were significantly lower in relation to initial values. In patients with stable disease, difference was found only in the level of proteins being lower after the treatment. In patients with disease progression, values of aspartate aminotransferase and bilirubin were significantly increased after completed treatment. Conclusion: Treatment responses are not completely associated with the level of liver function test parameters. The only parameter which correlated with treatment response is gamma-glutamyltransferase. Its decrease is accompanied with disease regression.